Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma

• Published in: Oncotarget Vol. 7; no. 2; pp. 1486 - 1499
• Main Authors: Darb-Esfahani, Silvia, Kunze, Catarina Alisa, Kulbe, Hagen, Sehouli, Jalid, Wienert, Stephan, Lindner, Judith, Budczies, Jan, Bockmayr, Michael, Dietel, Manfred, Denkert, Carsten, Braicu, Ioana, Jöhrens, Korinna
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 12.01.2016
• Subjects: B7-H1 Antigen - analysis; B7-H1 Antigen - genetics; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Carcinoma - chemistry; Carcinoma - genetics; Carcinoma - immunology; Carcinoma - therapy; Databases, Genetic; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Lymphocytes, Tumor-Infiltrating - chemistry; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - pathology; Middle Aged; Neoplasm Grading; Neoplasms, Cystic, Mucinous, and Serous - chemistry; Neoplasms, Cystic, Mucinous, and Serous - genetics; Neoplasms, Cystic, Mucinous, and Serous - immunology; Neoplasms, Cystic, Mucinous, and Serous - therapy; Ovarian Neoplasms - chemistry; Ovarian Neoplasms - genetics; Ovarian Neoplasms - immunology; Ovarian Neoplasms - therapy; Programmed Cell Death 1 Receptor - analysis; Programmed Cell Death 1 Receptor - genetics; Research Paper; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Time Factors; Tissue Array Analysis; PD-L1; tumor-infiltrating lymphocytes; ovarian; PD-1; high grade serous carcinoma
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.6429

Antibodies targeting the checkpoint molecules programmed cell death 1 (PD-1) and its ligand PD-L1 are emerging cancer therapeutics. We systematically investigated PD-1 and PD-L1 expression patterns in the poor-prognosis tumor entity high-grade serous ovarian carcinoma. PD-1 and PD-L1 protein expression was determined by immunohistochemistry on tissue microarrays from 215 primary cancers both in cancer cells and in tumor-infiltrating lymphocytes (TILs). mRNA expression was measured by quantitative reverse transcription PCR. An in silico validation of mRNA data was performed in The Cancer Genome Atlas (TCGA) dataset. PD-1 and PD-L1 expression in cancer cells, CD3+, PD-1+, and PD-L1+ TILs densities as well as PD-1 and PD-L1 mRNA levels were positive prognostic factors for progression-free (PFS) and overall survival (OS), with all factors being significant for PFS (p < 0.035 each), and most being significant for OS. Most factors also had prognostic value that was independent from age, stage, and residual tumor. Moreover, high PD-1+ TILs as well as PD-L1+ TILs densities added prognostic value to CD3+TILs (PD-1+: p = 0.002,; PD-L1+: p = 0.002). The significant positive prognostic impact of PD-1 and PD-L1 mRNA expression could be reproduced in the TCGA gene expression datasets (p = 0.02 and p < 0.0001, respectively). Despite their reported immune-modulatory function, high PD-1 and PD-L1 levels are indicators of a favorable prognosis in ovarian cancer. Our data indicate that PD-1 and PD-L1 molecules are biologically relevant regulators of the immune response in high-grade serous ovarian carcinoma, which is an argument for the evaluation of immune checkpoint inhibiting drugs in this tumor entity.